CIC bioGUNE researchers describe a new microRNA determinant of response to sorafenib in patients with hepatocellular carcinoma

Identification of the miR-518d-5p molecule in blood is associated with increased resistance to sorafenib treatment and reduced overall survival in patients with hepatocellular carcinoma.

Inhibition of this molecule by genomic approaches is associated with increased sensitivity to sorafenib in human hepatoma cells and in preclinical experimental models of liver cancer.

The study findings have been published in the journal Cell Death and Disease.

(Bilbao, 9 June 2021). Researchers from the Liver Disease Laboratory at CIC bioGUNE, a member of the Basque Research & Technology Alliance (BRTA), have described a new microRNA, a gene expression regulator molecule, which determines the response of patients with hepatocellular carcinoma to sorafenib, a drug for the treatment of liver cancer.

The study, led by Dr Malu Martínez Chantar of CIC bioGUNE and of the Biomedical Research Centre Network for Liver and Digestive Diseases (CIBEREHD), alongside first authors Dr Pablo Fernández Tussy, Dr Rubén Rodríguez Agudo and Dr David Fernández (CIC bioGUNE-CIBEREHD), has been published in the journal Cell Death and Disease.

This international collaborative study has identified increased levels of miR-518d-5p (gene expression regulator molecule) in serum in patients with liver cancer. The identification of this molecule in blood is associated with increased resistance to treatment with the drug sorafenib and reduced overall survival in patients with hepatocellular carcinoma. Likewise, miR-518d-5p inhibition by genomic approaches may be related to an increase in the sensitivity of human hepatoma cells to sorafenib, as well as in preclinical experimental models of liver cancer.

"Micro-RNAs (miRNAs) are regulatory molecules of gene expression. A single miRNA is capable of modulating the expression of multiple genes involved in processes associated with the development of a multifactorial pathology. Thanks to their broad spectrum of action, these molecules could be used as new therapeutic tools for the treatment of complex diseases," explains Dr Malu Martínez Chantar.

Sixth most common cancer worldwide

Hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide and the third leading cause of cancer-related death. Despite recent progress in HCC treatment, the long-term survival and well-being of patients remain major challenges for the medical and scientific world. Although sorafenib is one of the first-line systemic drugs for HCC treatment, the direct relation between the use of this drug and the survival of those patients treated with it depends on the patients’ baseline characteristics. Therefore, recognising the specific signalling mechanisms of tumours is essential to improve and predict, in this case, the activity of sorafenib. Identifying the main causes of drug resistance would be highly beneficial to guide a personalized HCC treatment, thereby enabling an accurate stratification of patients enrolled in associated clinical trials.

Participants in this research work, led by the CIC bioGUNE Liver Disease laboratory headed by Dr. Malu Martínez-Chantar (CIC bioGUNE and the Biomedical Research Centre Network for Liver and Digestive Diseases, CIBEREHD), also include the Precision Medicine Laboratory and the Inflammation and Macrophage Plasticity Laboratory (CIC bioGUNE); Laboratory of Experimental Hepatology and Drug Targeting (HEVEPHARM), University of Salamanca; BCLC (Liver Cancer), Hospital Clínico-IDIBAPSA; the Liver Unit of the Institut d'Investigacions Biomèdiques August Pi I Sunyer; Hospital Clinic; Universitat de Barcelona/ University of Barcelona; the Northern Institute for Cancer Research, the Medical School and the University of Newcastle (Newcastle-upon-Tyne, UK); the Department of Gastroenterology, Azienda Ospedaliero-Universitaria & University of Modena and Reggio Emilia (Modena, Italy); the Department of Liver and Gastrointestinal Diseases, Biodonostia Research Institute; Hospital Universitario Donostia/ University Hospital of San Sebastían, Universidad del País Vasco-Euskal Herriko Unibertsitatea/ University of the Basque Country (Donostia-San Sebastián); Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center (Los Angeles, USA); TGF-β and Cancer Group, Oncobell Programme, Bellvitge Biomedical Research Institute (IDIBELL) and the University of Barcelona; Instituto de Salud Carlos III; Research Institute for Medicines (iMed. ULisboa), the Faculty of Pharmacy, Universidade de Lisboa/ University of Lisbon; IK4-Tekniker; and Ikerbasque, Basque Foundation for Science.

About CIC bioGUNE

The Centre for Cooperative Research in Biosciences (CIC bioGUNE), located in the Bizkaia Technology Park, is a biomedical research organisation conducting cutting-edge research at the interface between structural, molecular and cell biology, with a particular focus on generating knowledge on the molecular bases of disease, for use in the development of new diagnostic methods and advanced therapies. CIC bioGUNE has been accredited as a “Severo Ochoa Centre of Excellence”, the highest level of recognition for centres of excellence in Spain.

About the BRTA
The BRTA is an alliance made up of 4 collaborative research centres (CIC bioGUNE, CIC nanoGUNE, CIC biomaGUNE and CIC energiGUNE) and 12 technology centres (Azterlan, Azti, Ceit, Cidetec, Gaiker, Ideko, Ikerlan, Lortek, Neiker, Tecnalia, Tekniker and Vicometch), with the aim of developing advanced technological solutions for Basque companies.

With the support of the Basque Government, the SPRI Group and the Provincial Councils of the three regional provinces, the alliance seeks to promote collaboration among its centres, to strengthen the conditions to generate and transfer knowledge to companies, contributing to their competitiveness, and to spread Basque scientific and technological capacity.

BRTA has a staff of 3,500 professionals, accounts for 22% of the Basque Country’s R&D investment, generates an annual turnover of over EUR 300 million and files 100 European and international patents per year.

CIC bioGUNE, member of the Basque Research & Technology Alliance (BRTA)

About the CIBEREHD

CIBER (the Biomedical Research Centre Network), co-funded by the European Regional Development Fund (ERDF), is part of the Instituto de Salud Carlos III/ Carlos III Health Institute of the Ministry for Science, Innovation and Universities. The purpose of the Biomedical Research Centre Network for Liver and Digestive Diseases (CIBEREHD) is to promote and protect health by fostering research. This activity covers both basic research and clinical and translational aspects, and is based on the subject of liver and digestive diseases with the aim of innovating in their prevention and promoting relevant scientific and health advances through the collaboration of leading Spanish groups.

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